Protease Inhibitors' Metabolic Side Effects

[In the last few months we have heard increasing anecdotal
reports of a condition which has been named "Crix belly."
People may gain 40 pounds or more of fat remarkably quickly
in the lower abdomen, and there may also be some muscle
wasting in the arms and legs. The cause is unknown. This
problem was not seen before the use of protease inhibitors;
it is not known if it is associated primarily with indinavir
(Crixivan(R)), for which it was named, or if it may be caused
by other protease inhibitors as well. Nothing has been
published so far.

Last month we asked Lisa Capaldini, M.D., an AIDS physician
in San Francisco, what she was seeing that our readers should
know more about. She said that more attention was needed to
certain lipid (fat) and other metabolic problems which appear
to be related to protease inhibitor therapy.

The interview below was conducted on August 8, 1997 and went
to press four days later. Because this information is so new,
the picture could change rapidly over the next few weeks or
months. Those seeing this article at a future time should
seek out the most current information then available.]

ATN: What have you seen of metabolism problems with the
protease inhibitors?

Dr. Capaldini: So far we have identified three metabolic
disorders associated with protease inhibitor therapy as a
class. First we saw high triglycerides; triglycerides are one
of the two kinds of lipids, or fats, we measure in the blood.
Most peoples' triglyceride level runs between 100 and 200.
High triglycerides clinically can cause pancreatitis, and
have been found to be associated with (but not necessarily
cause) hardening of the arteries.

The second condition is high cholesterol in patients whose
previous cholesterol levels have either been normal, or as is
common with advanced HIV, low. The pattern of high
cholesterol is elevation of the "bad" or LDL cholesterol,
compared to the so-called "good" or HDL cholesterol. This is
the unfavorable pattern of LDL to HDL cholesterol associated
with hardening of the arteries, which can lead to heart
attacks, strokes, and peripheral vascular disease.

The third condition is high blood sugar. Usually the levels
are not high enough to cause symptoms or, to our knowledge,
to cause any of the complications associated with diabetes.
They are typically 110 to 150 -- which is not normal, but is
not in the range usually associated with symptoms, which
would be over 250.

We do know, from experience before the use of protease
inhibitor therapy, that HIV infection tends to predispose
people to both high blood sugars and high triglycerides. But
these were usually seen in patients with much disease
activity; they were almost a marker of HIV activity, and
therefore were often associated with patients with unusually
low cholesterol. On the other hand, it is clear that we did
not have the high cholesterol problem before protease
inhibitors were introduced.

It is worth mentioning that the endocrine system seems to be
one of the least affected systems of the body in HIV disease;
androgen deficiency is the only *common* endocrine disorder
associated with HIV disease. So it is a contrast that we are
seeing metabolic disorders as a result of our therapy, when
were not seeing much of these problems before.

"Crix Belly"

ATN: The Crix List, an electronic mailing list on the
Internet, has discussions of "Crix belly", reports of people
gaining 40 pounds or more in a very short time. [For more
information about the Crix list and how to join it, see
http://www.pinkpage.com/Crix/.]

Dr. Capaldini: No one understands what is causing this
condition. In appearance, "Crix belly" is closest to a
medical condition called Cushing's syndrome. People gain fat
on their lower belly and flanks, and often notice a loss of
muscle tissue in their arms and legs. This acquired condition
is associated with a disorder of cortisol, when you have too
much of it. There is no data yet to suggest that high
cortisol levels are being caused by Crixivan, but it is
remarkable how much Crix belly looks like Cushing's syndrome
in appearance.

This condition is very disturbing to patients, especially
those who started these drugs when they were asymptomatic or
minimally symptomatic, and now are hoping for long-term
benefits. Aesthetically it is disturbing; also, we do not
know what it means physiologically.

ATN: Does it seem to be more specific to Crixivan than to
other protease inhibitors?

Dr. Capaldini: That is what I have heard, and seen
anecdotally in my practice -- although about 70 to 80 percent
of my patients on protease inhibitors happen to be on
Crixivan, so whether the effect is specific to the drug, or
just seen with it more often because more patients are using
that drug, is not clear.

ATN: Has there been any experience in your practice with
people trying to control this condition either by
discontinuing protease inhibitor therapy entirely, or by
changing from Crixivan to another protease inhibitor?

Dr. Capaldini: I have no knowledge about that, either in my
practice or otherwise. I have two patients who have both had
terrific responses to Crixivan, in viral load and T-cell
improvements, and because of that are apprehensive about
switching, particularly given all the conflicting cross-
resistance data that is coming out. Despite that, at least
these two people in my practice are considering switching to
another protease inhibitor, with the hope that it is a
Crixivan-specific effect and that stopping the drug will
reverse it. But we do not yet know whether it is drug
specific, or whether it will reverse if the drug is
discontinued.

ATN: Have you heard from Merck about this effect?

Dr. Capaldini: Not yet. I think the news is just starting to
trickle down the anecdotal pathway. [Note: Merck is
interested in hearing from either physicians or patients
about this or any other problem with Crixivan. Call the Merck
National Service Center, 800/672-6372.]

Note that there is also a separate condition which has been
called Crixivan belly, which seems to be more associated with
the protease inhibitors as a class, not just Crixivan --
people getting bloating or heartburn or rapid transit time
diarrhea problems. But when people use the term Crix belly,
they are usually referring to getting fatty tissue in the
gut, with leg and arm muscle wasting.

Clinical Course, and Potential Treatments

ATN: About how often do these different metabolic problems
occur, and when in the course of the therapy?

Dr. Capaldini: The metabolic conditions tend to show up after
about a year of protease inhibitor therapy -- although I have
seen patients' cholesterol change from abnormally low, to
more normal for them, as early as three to six months into
therapy. At first I thought that was a good sign, indicating
that metabolism was returning to normal. It was only about
six months ago that my first patient had his cholesterol
level go from a normal range to a high range. In this
person's case, there is a strong family history of coronary
artery disease. But I have seen high cholesterol both in
patients with and without such family history.

ATN: How concerned are you?

(1) Cholesterol
Dr. Capaldini: It is important for patients taking protease
inhibitors to understand that simply having a high
cholesterol rarely results in harmful events (heart attacks,
strokes, and dysfunction of the peripheral blood vessels, a
condition called claudication). The vast majority of people
who have those problems have multiple risk factors, including
hypertension, diabetes, obesity, inactivity, and smoking. It
is unusual for somebody to have only one risk factor and have
anything come of it. On the other hand, the risk associated
with cholesterol depends on the level; if it gets quite high,
for example over 400, then even as an isolated risk factor it
can cause disease.

So no one should be stopping their protease inhibitor or
panicking because their cholesterol has risen from say 200 to
the 250 range. I have encouraged my patients to sit tight
until we can discover (1) is this a stable phenomenon, or is
it likely to get worse over time, and (2) are any adverse
clinical outcomes likely to result?

There are well tolerated, easy to take drugs that safely
lower cholesterol in the general population; they are called
HMG-CoA reductase inhibitors (lovastatin, etc.), and they
work by keeping the liver from recycling fat in the gut. They
are quite safe. There is probably an interaction between them
and ritonavir (Norvir(R)); but as we know there are very many
drug interactions with that drug. So we could treat this; the
real issue is should we treat it?

For people who have tried lipid-lowering drugs in the past,
the prior generation were poor; they were unpredictably
effective and tended to cause a lot of gastrointestinal side
effects. This newer class of drugs is both reliably effective
and amazingly safe. It may well be that for some patients,
adding one pill a day of these drugs is an appropriate
intervention; we just do not know yet.

(2) Triglycerides
Regarding the high triglyceride problem, most experts do not
intervene unless the level is over a thousand, or in some
cases over 500 -- around the threshold which may predispose
to pancreatitis. The treatment for high triglyceride is a
lipid-lowering drug called Lopid (generic name gemfibrozil);
it is usually very well tolerated, and is taken twice a day.

Some patients have found that they can get their
triglycerides from a high range to a lower range -- not
normal but safer -- by modifying how much fat they eat. For
patients who are not having trouble maintaining their weight,
that is a reasonable approach. But some patients need to keep
more fat in their diet just to maintain their weight; for
them the lipid-lowering drug might make sense.

(3) Blood Sugar
Concerning high blood sugar, many people are confused and
think that if their blood sugar is outside of the normal
range, they have to take medicine for it. That is not the
case. Most physicians do not treat a high blood sugar problem
unless it is causing symptoms or unless it is consistently
over 150. And for most of those who do need treatment, that
means taking a pill once or twice a day, and learning how to
do blood sugar monitoring. I have never had a patient on
protease inhibitor therapy get the severe form of diabetes
that was reported a couple months ago, where patients were
hospitalized with severe diabetic conditions. The patients I
have identified have had gradually escalating blood sugar,
usually with no symptoms at all, and it has been quite easy
to take care of.

(4) Crix Belly
ATN: Going back to the Crix belly problem, it might be useful
research to try lowering these values into the normal range
after someone had gained the first ten pounds or so, to see
if the problem might be stopped.

Dr. Capaldini: Because we have no idea what is causing this
problem, we do not have a handle on where to intervene.

Antiretroviral Treatment Strategies

ATN: Are these metabolic side effects changing your views on
treatment?

Dr. Capaldini: To me as a primary care doctor, these
metabolic phenomena are an excellent example of why the "hit
hard, hit early, it's the virus stupid" approach may not be
as straightforwardly correct as it looks. The argument behind
this strategy has been that (1) we know that HIV causes the
disease, and (2) we know that it is harder to control the
virus when there is more virus in the body, and (3) viral
load increases with time; therefore, it seems intuitively
obvious that everyone should be on combination therapy as
soon as they know they are HIV positive. Those of us who have
questioned that approach -- not its logic, but in how it
works clinically -- are concerned that we do not know the
long-term safety or benefits of these drugs, and that as a
general rule of thumb, the earlier in a disease you treat a
patient, the more problems you may have with long-term
medication side effects.

So these metabolic disorders, while they may not turn out to
be associated with any long-term problems, make me feel
uncertain about recommending combination therapy including
protease inhibitors to patients with very early disease. My
concern is *not* only because of any question about whether
we can control the virus long-term with current agents, but
because of the unknown trade-offs between early control of
viral production and the long-term consequences of medication
side effects.

In the old days of the nucleoside analogs, sequential
monotherapy, AZT and 3TC etc., when a drug caused a problem
it was a simple matter to stop giving it and replace it with
another drug. With protease inhibitors, these therapeutic
decisions are more complex. We do not feel it is safe to
decrease doses, because of the possibility of developing
viral resistance to the drugs -- especially because recent
data suggests that once a patient's virus becomes resistant
to one protease inhibitor, it may also be resistant to all of
the other currently available protease inhibitors. So that
makes changing dosages, stopping or starting these drugs,
quite a bit more problematic than with the other HIV drugs.

ATN: What should patients do now?

Dr. Capaldini: If they get these side effects, they should
*not* stop their drugs and then call their doctor. These
metabolic side effects do not seem to be causing any short-
term risk -- yet it is quite risky to stop and start protease
inhibitor therapy, because of the danger of the virus
becoming resistant. Unfortunately it will probably take six
to 12 months for us to even have practice guidelines for
these lipid disorders.

Discussion with Carl Grunfeld, M.D., Ph.D.

Note: After the interview AIDS Treatment News talked to Carl
Grunfeld, Professor of Medicine at the University of
California San Francisco, who is studying these conditions.
He emphasized several points:

* In 1992, before the protease inhibitors, his group reported
a 33% decrease in LDL cholesterol (a large decrease) due to
HIV infection. Abnormally high cholesterol levels which
people had anyway may be returning due to effective
antiretroviral treatment.

* His group first reported the high triglycerides associated
with HIV infection. Others reported that this effect was
increased with ritonavir (other drugs were not tested).

* The blood sugar problem is rare. And a full spectrum of
conditions has been reported; there does not seem to be any
pattern resulting from protease inhibitor treatment.

* The weight gain, etc. should not be called Crix belly,
because it may not be specific to Crixivan -- or even to
protease inhibitors as a class. A handful of cases may have
occurred before protease inhibitors. To him as an
endocrinologist it has not looked like Cushing's syndrome --
but if physicians suspect Cushing's syndrome, they should
test patients for that, and this issue could be settled.

* No one knows what is causing this condition; and so far, no
one has shown that it is harmful. Standard body composition
measurements have failed to show the nature of the problem.
As a next step in the research, Dr. Grunfeld suggested
measuring regional body composition, using CT, or MRI, or
possibly DEXA. Regional body composition is an experimental
technique, and protocols will need to be developed.

Taxol Approved for Kaposi's Sarcoma

On August 5 Bristol-Myers Squibb announced that the FDA had
approved Taxol(R) (paclitaxel) "for use in second-line
treatment of AIDS-related Kaposi's sarcoma." The drug had
already been approved for use in cancer treatment.

An independent analysis by Michael Marco of the Treatment
Action Group strongly supported the approval, noting that
"Taxol as second-line therapy has double the response rate
and twice as long duration of response as DaunoXome which is
indicated for first-line therapy." [Community Consensus
Position Paper Regarding Approval of Bristol-Meyers Squibb's
NDA for Taxol (Paclitaxel) for Second-Line Treatment of
Kaposi's Sarcoma in People With AIDS, July 23, 1997.]

San Francisco:Changes at Conant Medical Group

A confusing series of disputes, caused ultimately by changes
in the business of medicine, has led to the disbanding of the
Conant Medical Group [Dr. Conant's dermatology practice has
not been affected]. To assure continuity of care, some
patients will need to decide whom they want to stay with,
arrange for the transfer of their medical records, and
perhaps also change their designation of primary care
provider at their HMO. In case of doubt, contact your
provider's office to learn what actions, if any, you need to
take.

An August 7 letter to patients provided new contact
information for some of the providers formerly with the
Conant Medical Group. Virginia Cafaro, M.D., Jon Kaiser,
M.D., Lisa Lewis, M.D., Martin Kramer, PA-C, Pat Sanders,
FNP, and Gordon Sanford, PA-C., can now be reached through a
message number, 437-5433, fax 437-5434. They are located in a
new office at Davies Medical Center, Castro at Duboce, in San
Francisco.

Medical records for all former Conant Medical Group patients
are at the Potrero Hill Medical Group. Patients can obtain
copies of their records, or have them sent to the physician
of their choice. In case of questions, contact the Potrero
Hill Medical Group at 923-6560.

Note re Quest: Confusion has occurred because two different
HIV medical organizations in San Francisco are named Quest.
Margaret Poscher, M.D., asked us to clarify that "Quest, a
primary care group," which is owned by her, is entirely
separate from "Quest Comprehensive Health Care Systems,"
which purchased the Conant Medical Group. Dr. Poscher told us
that she has supported the concept of Quest Comprehensive
Health Care Systems creating a national HIV practice network,
but that it has no role in the management of her practice.

Comment: Managed Care

These difficulties at one of the leading HIV medical
practices in the country highlight the need for more public
and professional attention to issues of managed care and
other changes in medicine today. California is ahead of most
of the U.S. in the use of managed care -- so what happens
here, for better or for worse, has national importance.

Traditionally, physicians were usually paid for the services
they performed; a drawback of this system was the financial
incentive to overtreat, since the more procedures and tests
they used, the more the doctors got paid. To control the
resulting inflation of health-insurance costs, employers
started shifting to HMOs (health maintenance organizations),
which usually pay doctors a fixed amount per patient to
provide whatever care is necessary -- a system called
capitation. The drawback here is a financial incentive to
undertreat, and to avoid expensive patients.

Unless other arrangements are negotiated, capitation rates
are often the same for a patient with a serious condition
like HIV or cancer, as for a healthy person who needs little
medical care. This makes it impossible for an HIV specialty
practice to survive, since they will lose money on almost
every patient.

This is the pressure which is forcing specialists in HIV,
cancer, and some other fields to combine into large groups of
physicians. These physician groups can negotiate with HMOs to
handle the care of their HIV infected patients -- with or
without capitation -- at a rate which covers the cost of
care. Large groups can also cut costs and generate income in
ways which individual practitioners and small groups usually
cannot -- from economies of scale, to developing standard
protocols for both quality and efficiency, to running
clinical trials, to vertical integration with their own
laboratory, pharmacy, and other services (which individual
physicians or small groups are usually forbidden to do).

Few patients, physicians, or others involved think that these
changes are all bad, or all good. Clearly there are
potentials for kinds of abuses which particularly harm
persons who are seriously ill. Until we have workable
healthcare reform, public vigilance, advocacy, and sometimes
aggressive pressure will be required.

IDSA Annual Meeting, September 12-16, San Francisco

The Infectious Diseases Society of America will hold its
annual meeting in San Francisco, September 12-16. While not
focused on AIDS, there may be important new AIDS information
presented.

Registration is $230 non-member, with reduced rates for
members or for fellows in training. For more information,
call the IDSA at 703/299-0200.

The abstracts will be placed online starting the first day of
the meeting, at the IDSA site, http://www.idsociety.org.

A partial program is available there now.

1998 Retroviruses Conference:Deadlines Available Soon

Deadlines for registration, scholarship applications, and
community press applications for the 1998 Retroviruses
conference, planned for Chicago in early February, will be
released around August 15. They were not available when this
issue went to press on August 12, however.

The information will be posted on the World Wide Web,
www.retroconference.org.

AIDS Treatment NewsMust Increase Prices

by John S. James

AIDS Treatment News has not raised its individual
subscription price for over 10 years, since we started the
newsletter. Now we need an increase to assure our long-term
stability and independence. All our subscription prices will
increase up to 20%, starting September 1.

Grace Period for Current Subscribers

(1) If your renewal is currently due and you have received a
renewal notice dated before September 1, you can pay that
notice at the old rate -- even if you pay after September 1,
when the price for new subscribers goes up.

(2) Through September 15, any other current subscriber can
add up to one year to their subscription at the old rate. To
do this, call our office at 800/TREAT-1-2 or 415/255-0588,
Monday through Friday 10 a.m. to 4 p.m. Pacific time.

Consensus Letter: Peter Duesberg

by John S. James

Project Inform is circulating a consensus letter addressed to
the National Academy of Sciences, concerning "the continuing
public campaign of Peter Duesberg to convince the public,
people at risk of HIV infection, and people already infected
that HIV poses no threat to them and that current treatments
for the disease and recreational drug abuse are in fact the
cause of the disease." The immediate event which led to this
letter was the publication of large advertisements headlined
"Breakthrough Discoveries in Scientific HIV/AIDS Research" in
three gay newspapers in San Francisco. The ad, for a talk by
Dr. Duesberg on August 9, included "two symbols of scientific
credibility, the Seal of the University of California, and
reference to his 1986 appointment to the National Academy of
Sciences."

The letter has been endorsed so far by over 20 AIDS
organizations, including AIDS Project Los Angeles, San
Francisco AIDS Foundation, ACT UP/Golden Gate, AIDS Research
Alliance, Community Research Initiative on AIDS, and Critical
Path AIDS Project.

For a copy of the letter, which is still open for
endorsements, call Project Inform, 800/822-7422, or fax a
request to FAIR (Foundation for AIDS & Immune Research) in
Los Angeles, 310/471-4565.

Comment

We have become increasingly concerned about the promotion of
the idea that HIV is harmless, and that accepted medical
treatments are useless (or are the cause of AIDS). A number
of people are using these teachings to justify rejecting all
medical care for HIV infection, and ignoring guidelines for
reducing HIV transmission -- seriously threatening their own
health and that of others.

Nine years ago Dr. Duesberg spoke in the same auditorium, at
the Metropolitan Community Church in the Castro district of
San Francisco, sharing the stage with an advocate for
unconventional syphilis theories. At that time the building
was packed, with people struggling for space near a doorway
or window where they could hear. This year there were empty
seats in the auditorium, which holds about 300 -- although
the toll-free 888 number, set up to take registrations for
the free event, had announced that it was full.

We distributed the following flyer outside the meeting.

Duesberg -- And You

When you hear Peter Duesberg, Ph.D., you should know:

* Despite his tenure at the University of California, his
ideas are rejected by almost 100% of AIDS scientists and
doctors. They are not taken seriously.

* Dr. Duesberg and his followers are not medical doctors;
they do not treat patients. As far as we know, there is no
doctor in the U.S. or anywhere else who treats patients
according to Duesberg's ideas.

But Duesberg is an excellent, persuasive public speaker. He
knows how to sound reasonable, use humor, and include
statements that are true, important, and meaningful to
people. He offers an easy, comforting approach to HIV. This
is why he has been able to influence people to trust him and
reject their doctors' advice.

* New treatments have greatly reduced AIDS deaths,
hospitalizations, and other complications. Many people who
were disabled are now going back to work. Several years ago,
the BAY AREA REPORTER filled an obituary section every week
(as many as 37 death notices in a single week); in the last
year, there have usually been four or five in each issue,
some of them unrelated to AIDS. (The newspaper has not
changed its policy of immediately publishing all obituaries
received.)

* Competent medical care for AIDS does not necessarily mean
taking drugs; many patients are healthy without drugs and
choose to leave well enough alone for now, with their
doctor's support. What is important is to see a doctor who is
experienced with HIV, to be monitored so that options can be
considered and treatment started when it does become
necessary. Treatment for HIV infection, like treatment for
any serious illness, must be individualized for each patient.
No single approach or philosophy fits all.

* Unfortunately there is now an organized, well-financed
campaign which encourages people with HIV to reject
lifesaving medical care. People have heard Duesberg say that
HIV does not cause AIDS and that drugs do, and have rejected
all medical care for HIV infection (and safer-sex precautions
as well). Medical experts agree that without treatment,
almost everyone with HIV will ultimately progress to AIDS and
death. Persons who wait until they need emergency care have
much worse treatment prospects than those who start earlier.

For More Information

Do not make life and death decisions after hearing only one
point of view -- especially a view entirely rejected by
medical professionals. Many credible AIDS resources are
available in San Francisco. Some examples:

* Project Inform runs a hotline (558-9051, 9 a.m. to 5 p.m.
Monday through Friday, or Saturday 10 to 4, Pacific time). It
also has excellent written information available without
charge, and a volunteer program which includes training on
AIDS, HIV, and treatment options.

* ACT UP/Golden Gate meets in the Castro every Tuesday
evening, focusing on getting new treatments developed faster,
and on access, insurance, and housing issues. For
information, call 252-9200.

* Healing Alternatives Foundation has an AIDS treatment
library at Market St. near Valencia, with information about
both mainstream and alternative treatments. For schedule and
other information, call their voicemail at 626-2316.

* Also note the National AIDS Hotline, run by the U.S.
Centers for Disease Control, where you can speak to
information specialists who can answer questions about AIDS
or provide local referrals; call 800/342-AIDS, 24 hours a day
every day of the year. [For Spanish-speaking information
specialists, call 800/344-SIDA, 5 a.m. to 11 p.m. Pacific
time every day; for TTY, 800/AIDS-TTY, Monday through Friday
7 a.m. to 7 p.m. Pacific time.]

* For a point-by-point refutation of Duesberg's statements,
see THE EVIDENCE THAT HIV CAUSES AIDS, an 8-page fact sheet
prepared and published by the U.S. National Institutes of
Health, at http://www.niaid.nih.gov/factsheets/evidhiv.htm.
For details and references, see THE RELATIONSHIP BETWEEN THE
HUMAN IMMUNODEFICIENCY VIRUS AND THE ACQUIRED
IMMUNODEFICIENCY SYNDROME, also by the NIH; this report, with
about 20 pages of text and about 500 references, is at
http://www.niaid.nih.gov/publications/hivaids/all.htm. These
papers were published in 1995, and would be stronger today
since new information (including results from improved
treatments) could be included.

Statement of Purpose:AIDS Treatment News reports on experimental and
standard treatments, especially those available now. We
interview physicians, scientists, other health
professionals, and persons with AIDS or HIV; we also
collect information from meetings and conferences,
medical journals, and computer databases. Long-term
survivors have usually tried many different treatments,
and found combinations which work for them. AIDS
Treatment News does not recommend particular
therapies, but seeks to increase the options available.

Copyright 1997 by John S. James. Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
quotations are used.

This article was provided by AIDS Treatment News.
You can find this article online by typing this address into your Web browser:
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